Case
A 9-month-old female presented with hepatosplenomegaly and was found to have hyperleukocytosis (WBC 1100 k/µL), anemia (2.4 g/dL), and thrombocytopenia (27 k/µL). Flow cytometry confirmed the diagnosis of pro-B ALL and cytogenetics revealed a KMT2A rearrangement (4;11 translocation). She was initiated on therapy per Children’s Oncology Group study AALL15P1 (ClinicalTrials.gov Identifier: NCT02828358, Interfant-06 backbone10 with addition of azacitidine blocks). Post-induction minimal residual disease (MRD) analysis was positive for residual B-ALL (0.73% by flow cytometry; persistent 4;11 translocation by Fluorescence in situ Hybridization [FISH]). She continued therapy per AALL15P1 protocol with azacitidine block 1, consolidation, azacitidine block 2, and interim maintenance 1, after which she had refractory disease with circulating blasts.
Given persistent disease, CD19 CAR-T therapy was the next intended therapy. T-cells were collected following marrow recovery after interim maintenance 1. While awaiting ex-vivo CAR-T manufacturing, she received venetoclax, vincristine, dexamethasone, and pegaspargase.11 She tolerated this protocol well, only complicated by neutropenia and pre-septal cellulitis which responded well to antibiotics. End of course bone marrow evaluation with B-cell flow-cytometry MRD analysis was negative. However, cytogenetics revealed persistent KMT2A- r in 14% of cells. Flow cytometric analysis demonstrated AML with monocytic differentiation, representing 39% of marrow cells. Given the lack of CD19, Tisagenlecleucel was not infused.
Instead, a myeloid-directed individualized therapy was initiated based on the VENAML study12, cohort C consisting of venetoclax, cytarabine, and azacitidine. End of course bone marrow evaluation was negative for abnormal myeloid blasts but B-ALL MRD show 12.6% abnormal lymphoblasts, indicating a reversion back to a lymphoid immunophenotype. Given that her disease was positive for CD19 and CD33, she was initiated on therapy consisting of a combination of blinatumomab and gemtuzumab13. End of course marrow demonstrated 79% B-cell lymphoblasts that were now CD19 negative by flow cytometry.
She then received another therapeutic approach with myeloid and lymphoid directed components, including both CPX-351 (liposomal daunorubicin and cytarabine) and Inotuzumab. Her course was complicated by neutropenia and Streptococcus mitis bacteremia that did not require intensive care unit support. At the end of this course, the bone marrow biopsy was morphologically normal and flow-based MRD testing was negative on both B-ALL and AML MRD. Furthermore, FISH for KMT2A rearrangement was negative for the first time during her treatment. Sequencing for rearrangements of the immunoglobulin receptor (ClonoSeq, Adaptive Biotechnologies) remained positive for low level residual disease (48 residual clones per million nucleated cells). Her CSF was positive for blasts, but cleared with additional intrathecal cytarabine, hydrocortisone, and methotrexate while preparing for transplant.
She then proceeded to an unrelated umbilical cord transplant. Post-transplant course was complicated by sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), and multifocal pneumonia resulting in ARDS requiring ECMO support. Her leukemia relapsed on day +37 from transplant, with a conversion back to a myeloid immunophenotype. Cytogenetics redemonstrated her KMT2Arearrangement. Ultimately, she died on post-transplant day +57 from multi-organ failure.